Irak4 modulators

ABSTRACT

Compounds of Formula 0, and stereoisomers and pharmaceutically acceptable salts thereof, as well as methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of PCT/EP2018/066316, filed Jun. 19, 2018 which claims the benefit of priority to International Patent Application No. PCT/CN2017/089359, filed Jun. 21, 2017, both of which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

This invention pertains to compounds useful for inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4).

BACKGROUND OF THE INVENTION

TIR-domain (Toll-Interleukin 1 Receptor-domain) containing cell surface receptors such as the Toll-like receptors (TLR) and the IL-1 and IL-18 receptors play critical roles in innate immunity and have been implicated in the pathogenesis of autoimmunity. TLRs, for example, recognize pathogenic or endogenous ligands and provide a requisite signal for dendritic cell maturation and antigen presentation to T cell. Similarly, proteins that mediate signaling from these receptors have also been shown to play important roles in the pathogenesis of autoimmune disorders. For example mice deficient in MyD88, an adaptor protein that directly interacts with the TIR domain, are more susceptible to bacterial, fungal and parasitic infections. In addition, MyD88 deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and streptococcal cell wall-induced arthritis.

The Interleukin-1 Receptor Associated Kinase (IRAK) family is comprised of four family members IRAK1, IRAK2, IRAK3 (also termed IRAK-M), and IRAK4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain. Whereas IRAK1 and IRAK4 have kinase activity, IRAK2 and IRAK3 are catalytically inactive. Upon activation of their upstream cognate receptors, IRAK4 is thought to phosphorylate IRAK1, resulting in the activation and autophosphorylation of IRAK1 and subsequent phosphorylation of downstream substrates. The hyperphosphorylation of IRAK1 directs its dissociation from the receptor complex and its eventual ubiquitylation and proteasomal degradation. Phosphorylation of downstream substrates such as Pellino-2 ultimately leads to the activation of the MAPKs such as p38 and c-Jun N-terminal kinase (JNK) and NF-kB followed by production of pro-inflammatory cytokines, chemokines, and destructive enzyme.

The role of IRAK4 in innate immunity and in the pathogenesis of autoimmune diseases is emerging. See, e.g., Li et al., “IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase,” PNAS 2002, 99(8), 5567-5572; and Flannery et al., “The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling,” Biochem Pharm 2010, 80(12), 1981-1991. Patients with destabilizing or null mutations in IRAK4 demonstrate defects in TLR signaling and the production of pro-inflammatory cytokines such as IL-1 and TNF as well as antiviral cytokines such as IFNα and IFNβ. These patients demonstrate an increased susceptibility to gram-positive bacterial infections although they are generally resistant to gram-negative bacterial, viral, and fungal infections. Similarly, IRAK4 deficient mice have defects in TLR- and IL-1-mediated cytokine production and exhibit an increased susceptibility to infection. IRAK1 deficient mice demonstrate a loss of responsiveness to lipopolysaccharides (LPS), IL-1, and IL-18 as well as impaired Th1 development. These mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation.

Accordingly, compounds that modulate the function of IRAK4 represent an attractive approach to the development of therapeutic agents for the treatment of diseases such as inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus, diabetes, obesity, allergic disease, psoriasis, asthma, graft rejection, cancer and sepsis.

SUMMARY OF THE INVENTION

One aspect of the invention includes a compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,

R¹ is C₁₋₆alkoxy, oxetanyl, —NR^(x)R^(y), or a 6-membered heteroaryl that is optionally substituted with R^(z);

R² is halogen, oxo, CN, OH, C₁₋₆alkyl, —(C₀₋₃alkyl)-C₃₋₆cycloalkyl group, a —(C₀₋₃alkyl)-3-11 membered heterocyclic group, —NR^(a)R^(b), —NR^(c)C(O)R^(f), —NR^(e)S(O)₁₋₂R^(f), —C(O)(C₁₋₃alkyl), —C(O)NR^(c)R^(d), —C(O)OR^(f), —S(O)₁₋₂NR^(c)R^(d), or —(C₀₋₃alkyl)-OP(O)(OC₁₋₃alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen; oxo; CN; OR^(f); C₁₋₃haloalkoxy; —C(O)(C₁₋₃alkyl); —S—C₁₋₃alkyl; or C₁₋₃alkyl optionally substituted with OH, halogen, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, or a 3-8 membered heterocyclic group,

ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 6-membered saturated or partially saturated heterocyclic group, or a 9-membered bicyclic heteroaryl that comprises at least two heteroatoms selected form the group consisting of N, O, and S, wherein ring A is optionally substituted with R^(m); provided ring A is not an optionally substituted 9-membered bicyclic heteroaryl of the following formula,

R^(a), R^(b), R^(c) and R^(d) are, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), or —S(O)₁₋₂R^(f), or R^(c) and R^(d) are taken together to form a 5-8 membered heterocyclic group,

-   -   wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group,         or heteroaryl ring is independently optionally substituted with         halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy,         C₁₋₃haloalkoxy, —OR^(f), —NR^(g)R^(h), or a 5-6 membered         monocyclic heteroaryl ring;

R^(e) is, independently at each occurrence, hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(f) is, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(e), or —NR^(g)R^(h);

R^(g) and R^(h) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

each R^(m) is, independently at each occurrence, halogen; oxo; CN; —OR^(v); —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —N^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀ cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃ alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C₁₋₃alkyl;

R^(n), R^(p), R^(r) and R^(s) are, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₆6cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R^(v), —C(O)OR^(v), —C(O)NR^(t)R^(u), or —S(O)₁₋₂R^(v), or R^(r) and R^(s) are taken together to form a 5-8 membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(v), —NR^(t)R^(u), or a 5-6 membered monocyclic heteroaryl ring;

R^(t) and R^(u) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(v) is, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(w), or —NR^(t)R^(u); and

R^(w) is, independently at each occurrence, hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(x) and R^(y) are, independently at each occurrence, C₁₋₆alkyl, or R^(x) and R^(y) are taken together to form a 6-membered heterocyclic group that is optionally substituted with R^(z);

each R^(z) is, independently at each occurrence, halogen; oxo; CN; —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃ alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C₁₋₃alkyl.

Also provided is a pharmaceutical composition that comprises a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

Another aspect includes a method of preventing, treating, or lessening the severity of a disease or condition responsive to the inhibition of IRAK4 in a patient, comprising administering to the patient a therapeutically effective amount of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention.

Another aspect includes a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention.

Another aspect includes a method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention. In one aspect the disease is selected from the group consisting of Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

Another aspect includes a method for treating endometriosis in a patient, comprising administering to the patient a therapeutically effective amount of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention in therapy, such as the treatment of an inflammatory disease, an autoimmune disease, endometriosis, or cancer.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention in the treatment of an inflammatory disease.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for the preparation of a medicament for the treatment of an inflammatory disease.

Another aspect includes a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for use in the treatment of an inflammatory disease.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention in the treatment of cancer.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for the preparation of a medicament for the treatment of cancer.

Another aspect includes a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for use in the treatment of cancer.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention in the treatment of endometriosis.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for the preparation of a medicament for the treatment of endometriosis.

Another aspect includes a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for use in the treatment of endometriosis.

Another aspect includes a method of inhibiting IRAK4 in a cell, ex vivo, comprising contacting the cell with a compound, stereoisomer, or pharmaceutically acceptable salt of the invention.

Another aspect includes a method of inhibiting IRAK4 in a patient in need of therapy, comprising administering to the patient a compound, stereoisomer, or pharmaceutically acceptable salt of the invention.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention to inhibit IRAK4.

Another aspect includes the use of a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for the preparation of a medicament for inhibiting IRAK4.

Another aspect includes a compound, stereoisomer, or pharmaceutically acceptable salt of the invention for use in inhibiting IRAK4.

Another aspect includes a kit for treating a disease or disorder responsive to the inhibition of IRAK4. The kit can comprise a first pharmaceutical composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt of the invention, and instructions for use.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.

The term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted. In one example, the alkyl radical is one to eighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, or C₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH3), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl (—CH₂CH₂CH₂CH₂CH₂CH₂CH₃) and 1-octyl (—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃). In some embodiments, substituents for “optionally substituted alkyls” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms. One example includes aryl groups having 6-14 carbon atoms. Another example includes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl. Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five substituents, for example, 1-2, 1-3 or 1-4 substituents, such as chosen from groups specified herein (see “optionally substituted” definition), such as F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list. Examples of the term “substituted phenyl” include a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl, a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl” represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, 2-chloro-5-difluoromethoxy and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonyl amino.

The terms “compound(s) of the invention,” and “compound(s) of the present invention” and the like, unless otherwise indicated, include compounds of Formula 0 and the compounds of Table 1, including stereoisomers (including atropisomers), geometric isomers, tautomers, solvates, metabolites, isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugs thereof In some embodiments, solvates, metabolites, isotopes or prodrugs are excluded, or any combination thereof.

“Cycloalkyl” refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₈, C₃-C₁₀ or C₅-C_(10.) In other examples, the cycloalkyl group, as a monocycle, is C₃-C₈, C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as a bicycle, is C₇-C₁₂. In another example, the cycloalkyl group, as a spiro system, is C₅-C₁₂. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spiro cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. In some embodiments, substituents for “optionally substituted cycloalkyls” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic or spiro, saturated, partially saturated or unsaturated, aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl), ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles, e.g., 5-6 membered heteroaryl. In another example, heterocyclyl includes 3-11 membered heterocycloyalkyls, such as 4-11 membered heterocycloalkyls. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO₂), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR₄]⁺Cl⁻, [NR₄]⁺ OH⁻). Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example heterocycle groups. Heterocycles may be optionally substituted. For example, substituents for “optionally substituted heterocycles” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or 6-membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed. Table 7-2 [1985]. Included in the definition are bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, a heterocyclic group, or a cycloalkyl, wherein the bicyclic group is joined to the remainder of the molecule at any position of the bicyclic group. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, i midazol[1,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. Heteroaryl groups can be optionally substituted. In some embodiments, substituents for “optionally substituted heteroaryls” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH3, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

In particular embodiments, a heterocyclyl group is attached at a carbon atom of the heterocyclyl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.

The term “alkoxy” refers to a linear or branched monovalent radical represented by the formula —OR in which R is alkyl, as defined herein. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di- and tri-fluoromethoxy and cyclopropoxy. “Haloalkoxy” refers to a haloalkyl group, as that term is defined herein, as R.

The term “alkanoyl” refers to group (alkyl)-C(═O)—, wherein alkyl is as defined herein. For example, C₁-C₆alkanoyl refers to a group of formula (C₁-C₅alkyl)-C(═O)—. Alkanoyl groups include, formyl, acetyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl, pentanoyl, 3-methylpentanoyl, and hexanoyl.

“Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule. In some embodiments, an arrow together with an asterisk is used in the manner of a wavy line to indicate a point of attachment.

In certain embodiments, divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise. For example, in the group —R¹—R²—R³, if the group le is described as —CH₂C(O)—, then it is understood that this group can be bonded both as R¹—CH₂C(O)—R³, unless specified otherwise.

The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.

Compounds of the invention may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulphonate, 2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate (camphor-10-sulphonate, for example (1S)-(+)-10-camphorsulfonic acid salt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulphonate), and pamoic (2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all living microorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

“Chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds of the invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are intended to be within the scope of the present invention. The term “hydrate” refers to the complex where the solvent molecule is water.

A “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

Metabolite products typically are identified by preparing a radiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

“Amino-protecting group” as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Particular amino protecting groups are Pmb (p-Methoxybenzyl), Boc (tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz (Carbobenzyloxy). Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected amino” refers to an amino group substituted with one of the above amino-protecting groups.

“Carboxy-protecting group” as used herein refers to those groups that are stable to the conditions of subsequent reaction(s) at other positions of the molecule, which may be removed at the appropriate point without disrupting the remainder of the molecule, to give the unprotected carboxy-group. Examples of carboxy protecting groups include, ester groups and heterocyclic groups. Ester derivatives of the carboxylic acid group may be employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such ester groups include substituted arylalkyl, including substituted benzyls, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4′ -dimethoxybenzhydryl, 2,2′,4,4′ -tetramethoxybenzhydryl, alkyl or substituted alkyl esters such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esters such as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonyl ethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. Another example of carboxy-protecting groups are heterocyclic groups such as 1,3-oxazolinyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected carboxy” refers to a carboxy group substituted with one of the above carboxy-protecting groups.

“Hydroxy-protecting group” as used herein refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g., TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected hydroxy” refers to a hydroxy group substituted with one of the above hydroxy-protecting groups.

Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

Another aspect includes prodrugs of the compounds of the invention including known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the compound of the present invention under physiologic conditions.

The term “prodrug” refers to a precursor or derivative form of a pharmaceutically active substance that is less efficacious to the patient compared to the parent drug and is capable of being enzymatically or hydrolytically activated or converted into the more active parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy” Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985). Prodrugs include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, and 5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy group, an alkylcarbonyl (—CO—R) group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl (—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, for example alkyl, alkylene or aryl, or a group having the Formula —C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same or different and are hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In a particular embodiment, the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention. Prodrugs may be prepared by reacting a compound of the present invention with an activated group, such as acyl groups, to bond, for example, a nitrogen atom in the compound to the exemplary carbonyl of the activated acyl group. Examples of activated carbonyl compounds are those containing a leaving group bonded to the carbonyl group, and include, for example, acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions are generally carried out in inert solvents at reduced temperatures such as −78 to about 50° C. The reactions may also be carried out in the presence of an inorganic base, for example potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, trimethylamine, triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester. As another example, compounds of the invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, alpha-amino(C₁-C₄)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

“Leaving group” refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (for example p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

A “subject,” “individual,” or “patient” is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, a mammal is a human. In embodiments comprising administration of a compound of to a patient, the patient is typically in need thereof.

The terms “inhibiting” and “reducing,” or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity (e.g., IRAK4 activity) compared to normal.

In some embodiments, a compound of Formula 0, such as a compound of Table 1, is selective for inhibition of IRAK4 over IRAK1. By “selective for inhibition” it is meant that the compound is at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, better inhibitor of IRAK4 activity compared to IRAK1 activity, or is at least a 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better inhibitor of IRAK4 activity compared to IRAK1 activity.

A “therapeutically effective amount” means an amount of a compound of the present invention, such as a compound of Formula 0, that (i) treats or prevents the particular disease, condition or disorder, or (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, and optionally (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In some embodiments, the therapeutically effective amount is an amount sufficient to decrease or alleviate the symptoms of an autoimmune or inflammatory disease (e.g., lupus). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth or kill existing cancer cells, it may be cytostatic or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) or determining the response rate (RR).

“Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In some embodiments, compounds of the invention, are used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function. “Inflammatory disorder” also refers to a pathological state mediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune responses. Accordingly, inflammatory disorders amenable to treatment with a compound of the present invention, such as a compound of Formula 0, encompass disorders associated with reactions of the specific defense system as well as with reactions of the nonspecific defense system.

“Specific defense system” refers to the component of the immune system that reacts to the presence of specific antigens. Examples of inflammation resulting from a response of the specific defense system include the classical response to foreign antigens, autoimmune diseases, and delayed type hypersensitivity responses mediated by T-cells. Chronic inflammatory diseases, the rejection of solid transplanted tissue and organs, e.g., kidney and bone marrow transplants, and graft versus host disease (GVHD), are further examples of inflammatory reactions of the specific defense system.

The term “nonspecific defense system” refers to inflammatory disorders that are mediated by leukocytes that are incapable of immunological memory (e.g., granulocytes, and macrophages). Examples of inflammation that result, at least in part, from a reaction of the nonspecific defense system include inflammation associated with conditions such as adult (acute) respiratory distress syndrome (ARDS) or multiple organ injury syndromes; reperfusion injury; acute glomerulonephritis; reactive arthritis; dermatoses with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents. Non-limiting examples of autoimmune diseases include rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage, or loss of tissue function resulting from allergy. “Arthritic disease” as used herein refers to any disease that is characterized by inflammatory lesions of the joints attributable to a variety of etiologies. “Dermatitis” as used herein refers to any of a large family of diseases of the skin that are characterized by inflammation of the skin attributable to a variety of etiologies. “Transplant rejection” as used herein refers to any immune reaction directed against grafted tissue, such as organs or cells (e.g., bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the present invention include methods for the treatment of disorders associated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus (including, but not limited to, cytokines, antigens or auto-antibodies) of a proliferative cellular response, the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines), or cell surface expression of new or increased numbers of mediators (including, but not limited to, major histocompatability antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, dendritic cells, Langerhans cells, and endothelial cells). It will be appreciated by persons skilled in the art that the activation of one or a combination of these phenotypes in these cells can contribute to the initiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treated according to the methods of this invention include, but are not limited to, asthma, rhinitis (e.g., allergic rhinitis), allergic airway syndrome, atopic dermatitis, bronchitis, rheumatoid arthritis, psoriasis, lupus, chronic obstructive pulmonary disease (COPD), contact dermatitis, chronic obstructive pulmonary disease and delayed hypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and related terms refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) and lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, diffuse large B-Cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin's, and associated metastases. Examples of neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocytosis, myelofibrosis, such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders. Examples of chemotherapeutic agents are well-known in the art and include examples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557, incorporated herein by reference. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, as well as combinations of two or more of them.

Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of the invention, one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention.

If any discrepancy exists between a structure and its name, the structure prevails.

The use of the term “or” is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicated otherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

IRAK4 Inhibitors

One aspect of the invention includes a compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,

R¹ is C₁₋₆alkoxy, oxetanyl, —NR^(x)R^(y), or a 6-membered heteroaryl that is optionally substituted with R^(z);

R² is halogen, oxo, CN, OH, C₁₋₆alkyl, —(C₀₋₃alkyl)-C₃₋₆cycloalkyl group, a —(C₀₋₃alkyl)-3-11 membered heterocyclic group, —NR^(a)R^(b), —NR^(e)C(O)R^(f), —NR^(e)S(O)₁₋₂R^(f), —C(O)(C₁₋₃alkyl), —C(O)NR^(c)R^(d), —C(O)OR^(f), —S(O)₁₋₂NR^(c)R^(d), or —(C₀₋₃alkyl)-OP(O)(OC₁₋₃alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen; oxo; CN; OR^(f); C₁₋₃haloalkoxy; —C(O)(C₁₋₃alkyl); —S—C₁₋₃alkyl; or C₁₋₃alkyl optionally substituted with OH, halogen, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, or a 3-8 membered heterocyclic group,

ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 6-membered saturated or partially saturated heterocyclic group, or a 9-membered bicyclic heteroaryl that comprises at least two heteroatoms selected form the group consisting of N, O, and S, wherein ring A is optionally substituted with R^(m); provided ring A is not an optionally substituted 9-membered bicyclic heteroaryl of the following formula,

R^(a), R^(b), R^(c) and R^(d) are, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), or —S(O)₁₋₂R^(f), or R^(c) and R^(d) are taken together to form a 5-8 membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(f), —NR^(g)R^(h), or a 5-6 membered monocyclic heteroaryl ring;

R^(e) is, independently at each occurrence, hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(f) is, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, —OR^(c), or —NR^(g)R^(h);

R^(g) and R^(h) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

each R^(m) is, independently at each occurrence, halogen; oxo; CN; —OR^(v); —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀ cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃ alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl, C₃₋₁₀ocycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C₁₋₃alkyl;

R^(n)R^(p), R^(r) and R^(s) are, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R^(v), —C(O)OR^(v), —C(O)NR^(t)R^(u), or —S(O)₁₋₂R^(v), or R^(r) and RS are taken together to form a 5-8 membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(v), —NR^(t)R^(u), or a 5-6 membered monocyclic heteroaryl ring;

R^(t) and R^(u) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(v) is, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(w), or —NR^(t)R^(u); and

R^(w) is, independently at each occurrence, hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(x) and R^(y) are, independently at each occurrence, C₁₋₆alkyl, or R^(x) and R^(y) are taken together to form a 6-membered heterocyclic group that is optionally substituted with R^(z);

each R^(z) is, independently at each occurrence, halogen; oxo; CN; —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(f)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃ alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl, C₃₋₁₀ocycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C₁₋₃alkyl.

In some embodiments, R¹ is —NR^(x)R^(y).

In some embodiments, R^(x) and R^(y) are taken together to form a 6-membered heterocyclic group that is optionally substituted with R^(z).

In some embodiments, R^(x) and R^(y) are taken together to form a morpholino group that is optionally substituted with R^(z).

In some embodiments, R¹ is a 6-membered heteroaryl that is optionally substituted with R^(z).

In some embodiments, R¹ is pyridyl that is optionally substituted with R^(z).

In some embodiments, R¹ is selected from the group consisting of

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, ring A is selected from the group consisting of

In some embodiments, ring A is selected from the group consisting of

In some embodiments, R^(m) is selected from the group consisting of chloro, oxo, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CN, methoxy, OH, isopropoxy, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-methoxyethyl, 2-hydroxyprop-2-yl, morpholino, 20methylmorpholino, and 1H-pyrrol-3-yloxy.

In some embodiments, R^(m) is 3-methylmorpholino.

In some embodiments, the compound, stereoisomer, or pharmaceutically acceptable salt is selected from the group consisting of

and stereoisomers and pharmaceutically acceptable salts thereof.

In some embodiments, the compound, stereoisomer, or pharmaceutically acceptable salt is selected from the compounds shown in Table 1 below, and from stereoisomers and pharmaceutically acceptable salts thereof.

TABLE 1 Exemplary compounds of the present invention. Salts of such compounds are also contemplated. See the Examples section for preparation of such compounds. # Structure Name 1

N-[6-morpholino-1-oxo-2-[rac-(2R)- 2-fluoro-3-hydroxy-3-methyl- butyl]isoindolin-5-yl]imidazo[1,2- b]pyridazine-3-carboxamide 2

2-methyl-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl] oxazole-4-carboxamide 3

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]-2- oxo-1H-pyridine-3-carboxamide 4

1-methyl-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]-2- oxo-pyridine-3-carboxamide 5

1-ethyl-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]-2- oxo-pyridine-3-carboxamide 6

1-isopropyl-N-[6-morpholino-l- oxo-2-[rac-(2R)-2-fluoro-3- hydroxy-3-methyl-butyl]isoindolin- 5-yl]-2-oxo-pyridine-3- carboxamide 7

1-cyclopropyl-N-[6-morpholino- 1-oxo-2-[rac-(2R)-2-fluoro-3- hydroxy-3-methyl-butyl] isoindolin-5-yl]-2-oxo-pyridine- 3-carboxamide 8

6-cyano-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy- 3-methyl-butyl]isoindolin-5-yl] pyridine-2-carboxamide 9

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 2-(4-pyridyl)oxazole-4- carboxamide 10

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 2-[rac-(3S)-3-methylmorpholin- 4-yl]oxazole-4-carboxamide 11

N-[6-(dimethylamino)-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy- 3-methyl-butyl]isoindolin-5-yl]- 6-isopropoxy-pyridine-2- carboxamide 12

4-hydroxy-N-[6-morpholino-1- oxo-2-[rac-(2R)-2-fluoro-3- hydroxy-3-methyl-butyl] isoindolin-5-yl]pyridine-2- carboxamide 13

N-[6-(dimethylamino)-1-oxo-2- [rac-(2R)-2-fluoro-3-hydroxy- 3-methyl-butyl]isoindolin-5-yl]- 6-pyrrolidin-3-yloxy-pyridine- 2-carboxamide 14

2-methyl-N-[6-(5-methyl-2- pyridyl)-1-oxo-2-[rac-(2R)-2- fluoro-3-hydroxy-3-methyl- butyl]isoindolin-5-yl]oxazole- 5-carboxamide 15

2-morpholino-N-[6-morpholino- 1-oxo-2-[rac-(2R)-2-fluoro-3- hydroxy-3-methyl-butyl] isoindolin-5-yl]oxazole-4- carboxamide 16

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 2-[rac-(3R)-3-methylmorpholin- 4-yl]oxazole-4-carboxamide 17

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 6-(trifluoromethyl)pyridine-2- carboxamide 18

N-[6-(dimethylamino)-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy- 3-methyl-butyl]isoindolin-5- yl]-6-(trifluoromethyl)pyridine- 2-carboxamide 19

N-[6-(dimethylamino)-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy- 3-methyl-butyl]isoindolin-5-yl]- 6-methoxy-pyridine-2- carboxamide 20

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl] thieno[2,3-b]pyrazine-7- carboxamide 21

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 6-[rac-(1R)-1-hydroxyethyl] pyridine-2-carboxamide 22

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 6-[rac-(1S)-1-hydroxyethyl] pyridine-2-carboxamide 23

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 6-[rac-(1R)-1-methoxyethyl] pyridine-2-carboxamide 24

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 6-[rac-(1S)-1-methoxyethyl] pyridine-2-carboxamide 25

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 6-(2,2,2-trifluoroethyl)pyridine- 2-carboxamide 26

5-methyl-N-[6-morpholino-1- oxo-2-[rac-(2R)-2-fluoro-3- hydroxy-3-methyl-butyl] isoindolin-5-yl]-4-oxo-pyrazolo [1,5-a]pyrazine-3-carboxamide 27

6-(1-hydroxy-1-methyl-ethyl)- N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl] pyridine-2-carboxamide 28

N-[6-isopropoxy-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 7-methyl-imidazo[1,2-b] pyridazine-3-carboxamide 29

7-methyl-N-[6-morpholino-1- oxo-2-[rac-(2R)-2-fluoro-3- hydroxy-3-methyl-butyl] isoindolin-5-yl]imidazo[1,2-b] pyridazine-3-carboxamide 30

N-[6-[4-(oxetan-3-yl)piperazin- 1-yl]-1-oxo-2-[rac-(2R)-2-fluoro- 3-hydroxy-3-methyl-butyl] isoindolin-5-yl]thieno[2,3-b] pyrazine-7-carboxamide 31

N-[6-[4-(oxetan-3-yl)piperazin- 1-yl]-1-oxo-2-[rac-(2R)-2-fluoro- 3-hydroxy-3-methyl-butyl] isoindolin-5-yl]thieno[3,2-d] pyrimidine-7-carboxamide 32

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- 1H-benzimidazole-4- carboxamide 33

5-chloro-1-methyl-N-[6- morpholino-1-oxo-2-[rac-(2R)- 2-fluoro-3-hydroxy-3-methyl- butyl]isoindolin-5-yl]pyrazole- 4-carboxamide 34

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]- [1,2,4]triazolo[1,5-a]pyridine- 5-carboxamide

Synthesis of IRAK4 Inhibitors

Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.

For illustrative purposes, reaction Schemes below provide routes for synthesizing the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used. Although some specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., more preferably from about 0° C. to about 125 ° C., and most preferably and conveniently at about room (or ambient) temperature, or, about 20° C.

Some compounds in following schemes are depicted with generalized substituents; however, one skilled in the art will immediately appreciate that the nature of the R groups can varied to afford the various compounds contemplated in this invention. Moreover, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims.

Methods of Treatment with and Uses of IRAK 4 Inhibitors

Compounds of the present invention are useful as IRAK4 inhibitors. Accordingly, in one embodiment is provided a method of contacting a cell, such as an ex vivo cell, with a compound of the present invention to inhibit IRAK4 activity in the cell.

Also provided is a pharmaceutical composition comprising a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent. Compounds of the invention, including pharmaceutical compositions comprising such compounds, may be used in the methods described herein.

Further provided is a method of preventing, treating, or lessening the severity of a disease or condition responsive to the inhibition of IRAK4 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

Also provided is a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

Further provided is a method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the disease is selected from the group consisting of Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

In some embodiments, other diseases and conditions responsive to the inhibition of IRAK4 that can be treated using a compound of the present invention include metabolic syndromes, atherosclerosis, and neurodegeneration.

Further provided is the use of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, in therapy. In some embodiments, use of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, is provided in the treatment of an inflammatory disease. In some embodiments, use of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment of an inflammatory disease. Furthermore, in some embodiments, a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, is provided for use in the treatment of an inflammatory disease.

In some embodiments, a disease or condition that may be treated is selected from the group consisting of acute kidney injury, acute respiratory distress syndrome, acute lung injury, adult onset Still's disease, allergic airway syndrome, allergic rhinitis, allograft rejection, asthma, atherosclerosis, atopic dermatitis, bronchitis, calcium pyrophosphate deposition disease (CPPD) also known as pseudo gout, cerebrovascular accident (e.g., stroke), chronic kidney disease, chronic obstructive pulmonary disease (COPD), contact dermatitis, Crohn's disease, cryopyrin-associated periodic syndromes (CAPS), cutaneous lupus, delayed hypersensitivity, diabetes, endometriosis, gout, gouty arthritis, graft vs host disease, graft rejection, inflammatory bowel disease (IBD), inflammatory myositis (e.g., polymyositis, dermatomyositis), interstitial lung disease, lupus, lupus nephritis, metabolic syndrome, multiple sclerosis, neurodegeneration, neuropathic pain, non-alcoholic fatty liver disease, obesity, psoriasis, rheumatoid arthritis, rhinitis, scleroderma, sepsis, Sjogren's syndrome, systemic lupus erythematosus, systemic onset juvenile idiopathic arthritis, systemic sclerosis and ulcerative colitis.

Also provided is a method of inhibiting IRAK4 in a patient in need of therapy, comprising administering to the patient a compound of the present invention.

Dosage & Administration

The present invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and at least one therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof, with the desired degree of purity may be formulated by mixing with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a dosage form at ambient temperature and at the appropriate pH. The pH of the formulation depends mainly on the particular use and the concentration of compound, but typically ranges anywhere from about 3 to about 8. In one example, a compound of Formula 0 is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of Formula 0 are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the severity of the disorder, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit IRAK4 activity. Typically such amount may be below the amount that is toxic to normal cells, or the patient as a whole.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.

A dose to treat human patients may range from about 0.1 mg to about 1000 mg of a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof. A typical dose may be about 1 mg to about 300 mg of the compound. A dose may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, H. C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, R. C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

For oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such as sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

In one embodiment, the pharmaceutical composition also includes at least one additional anti-proliferative agent.

An embodiment, therefore, includes a pharmaceutical composition comprising a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Combination Therapy

The compounds of Formula 0 may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula 0 such that they do not adversely affect each other. The combination therapy may provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.

The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.

Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof, and the use of at least one other treatment method. The amounts of the compound(s) of Formula 0 and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

In some embodiments, a second agent that may be employed in combination therapy with a compound described herein may be an inhibitor of Bruton's tyrosine kinase (BTK), such as a small molecule BTK inhibitor. In some embodiments, the second agent may be prednisone.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or “kit”, containing materials useful for the treatment of the diseases and disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof. The kit may further comprise a label or package insert on or associated with the container. The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of Formula 0 or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of Formula 0. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formula 0, such as tablets or capsules. Such a kit can include a number of unit dosages. An example of such a kit is a “blister pack”. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.

EXAMPLES

The following examples illustrate the preparation and biological evaluation of compounds within the scope of the invention. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Preparation of intermediate (R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one

a. 6-Chloro-2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-5-nitro-isoindolin-1-one

To a stirred solution of methyl 2-(bromomethyl)-5-chloro-4-nitro-benzoate (WO2013/079505, 4.5 g, 14.6 mmol) in methanol (90 mL) was added trimethylamine (2.95 g, 29.2 mmol) and (3R)-4-amino-3-fluoro-2-methyl-butan-2-ol (WO2014/074675, 3.5 g, 29.2 mmol). The mixture was stirred at 70° C. for 2 h under nitrogen. The reaction mixture was concentrated and purified by flash chromatography (40-63% ethyl acetate in petroleum ether) to afford 6-chloro-2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-5-nitro-isoindolin-1-one (quant. yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.03; (s, 1H), 4.91; (d, J=2.6 Hz, 1H), 4.75-4.58; (m, 2H), 4.47; (ddd, J=49.2, 9.4, 1.9 Hz, 1H), 4.00; (ddd, J=38.6, 14.9, 1.9 Hz, 1H), 3.74; (ddd, J=16.2, 14.9, 9.4 Hz, 1H), 3.34-3.23; (m, 1H), 1.18; (dd, J=4.9, 1.7 Hz, 6H). LCMS (ESI): m/z=317.1; [M+H]⁺.

b. 2-[(2R)-2-Fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-5-nitro-isoindolin-1-one

To a solution of 6-chloro-2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-5-nitro-isoindolin-1-one (1.3 g, 4.1 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.2 mmol) in dimethyl sulfoxide (20 mL) was added morpholine (715 mg, 8.21 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL×3). The organics were washed with brine (100 mL×2), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-60% ethyl acetate in petroleum ether) to afford 2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-5-nitro-isoindolin-1-one (1.3g, 86% yield) as a yellow solid. LCMS (ESI): m/z=368.2; [M+H]⁺.

c. (R)-5-Amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one

To a stirred solution of 2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-5-nitro-isoindolin-1-one (1.66 g, 4.52 mmol) in ethanol (30 mL) and water (6 mL) was added iron (1.26 g, 23 mmol) and ammonium chloride (1.21 g, 23 mmol). The mixture was stirred at 80° C. for 2 h under nitrogen, after which it was filtered and concentrated. The crude product was purified by chromatography on silica gel (eluting gradient: 0-5% methanol in dichloromethane) to give (R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoi soindolin-1-one (1.23 g, 81% yield) as an orange solid. LCMS (ESI): m/z=338.0; [M+H]⁺.

Example 1 (R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

A flask equipped with a stir bar under a nitrogen atmosphere was charged with imidazo[1,2-b]pyridazine-3-carboxylic acid (27 mg, 0.16 mmol). N,N-Dimethylformamide (1.0 mL) was added and the mixture was cooled 0° C. (7-Azabenzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (89 mg, 0.16 mmol) was added followed by 2,4,6-trimethylpyridine (0.022 mL, 0.16 mmol). (R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one (50 mg, 0.15 mmol) was added, and the ice bath was removed allowing the reaction to stir at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford (R)-N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide (9.3 mg, 13%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.41; (s, 1H), 9.01; (dd, J=4.6, 1.5 Hz, 1H), 8.76; (s, 1H), 8.52; (s,1H), 8.45; (dd, J=9.2, 1.5 Hz, 1H), 7.61; (s, 1H), 7.58; (dd, J=9.3, 4.6 Hz, 1H), 4.90; (s, 1H), 4.60-4.47; (m, 2H), 4.39; (dd, J=9.3, 1.8 Hz, 1H), 4.00; (dd, J=14.9, 1.6 Hz, 1H), 3.90-3.83; (m, 4H), 3.78-3.63; (m, 1H), 3.00-2.89; (m, 4H), 1.24-1.13; (s, 6H). MS (ESI): m/z=483.2; [M+1]⁺.

Example 2. (R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-2-methyloxazole-4-carboxamide

To a solution of (R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one (100 mg, 0.30 mmol), 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (225 mg, 0.59 mmol), N,N-diisopropylethylamine (0.34 mL, 2.1 mmol) in N,N-dimethylformamide (3 mL) was added 2-methyl-1,3-oxazole-4-carboxylic acid (56 mg, 0.44 mmol). The mixture was stirred at 30° C. for 12 h and filtered. The filtrate was concentrated and purified by reverse phase chromatography (Xtimate C18 150*25 mm*5 um, water (0.05% ammonia hydroxide v/v)-acetonitrile) to afford (R)-N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-2-methyloxazole-4-carboxamide (30 mg, 23%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.28; (s, 1H), 8.66; (s, 1H), 8.21; (s, 1H), 7.66; (s, 1H), 4.63-4.43; (m, 3H), 4.28-4.14; (m, 1H), 4.00 (t, J=4.4 Hz, 4H), 3.72-3.63; (m, 1H), 2.96; (t, J=4.0 Hz, 4H), 2.55; (s, 3H), 1.34; (s, 3H), 1.31; (s, 3H). LCMS (ESI): m/z=447.2; [M+H]⁺.

The following compounds were prepared using a procedure similar to that described in Example 2.

Ex. Name Structure NMR, MS 3 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoisoindolin- 5-yl)-2-oxo-1,2- dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 12.83 (d, J = 6 Hz, 1H), 12.68 (s, 1H), 8.78 (s, 1H), 8.50 (dd, J = 7.2, 2.0 Hz, 1H), 7.84-7.81 (m, 1H), 7.49 (s, 1H), 6.57 (t, J = 7.2 Hz, 1H), 4.57-4.46 (m, 3H), 3.96-3.70 (m, 5H), 3.68-3.64 (m, 1H), 2.88-2.86 (m, 4H), 1.18 (s, 3H), 1.17 (s, 3H). LCMS (ESI): m/z = 459.2 [M + H]⁺. 4 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoisoindolin- 5-yl)-1-methyl- 2-oxo-1,2- dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.74 (s, 1H), 8.83 (s, 1H), 8.62 (d, J = 7.6, 2.0 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J = 6.4, 2.0 Hz, 1H), 6.48-6.45 (m, 1H), 4.61-4.42 (m, 3H), 4.26- 4.13 (m, 1H), 4.06-4.05 (m, 4H), 3.72 (s, 3H), 3.69-3.55 (m, 1H), 2.97 (t, J = 4.4 Hz, 4H), 1.34 (s, 3H), 1.29 (s, 3H). LCMS (ESI): m/z = 473.2 [M + H]⁺. 5 (R)-1-Ethyl-N- (2-(2-fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin-5- yl)-2-oxo-1,2- dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.77 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 4.4 Hz, 1H), 7.66 (s, 1H), 6.59 (t, J = 7.2 Hz, 1H), 4.66-4.54 (m, 3H), 4.25-4.19 (m, 3H), 4.04 (m, 4H), 3.77-3.75 (m, 1H), 2.98-2.96 (m, 4H), 1.44 (t, J = 6.8 Hz, 3H), 1.30 (s, 6H). LCMS (ESI): m/z = 487.2 [M + H]⁺. 6 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-1- isopropyl-2- oxo-1,2- dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.05 (dd, J = 6.4, 1.6 Hz, 1H), 7.64 (s, 1H), 6.63 (t, J = 7.2 Hz, 1H), 5.41- 5.38 (m, 1H), 4.87-4.44 (m, 3H), 4.14-4.03 (m, 5H), 3.76- 3.70 (m, 1H), 2.97-2.95 (m, 4H), 1.48 (d, J = 6.4 Hz, 6H), 1.30 (s, 6H). LCMS (ESI): m/z = 501.3 [M + H]⁺. 7 (R)-1-Cyclopropyl- N-(2-(2-fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin-5- yl)-2-oxo-1,2- dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.74 (s, 1H), 8.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.94 (dd, J = 6.8, 2.0 Hz, 1H), 7.65 (s, 1H), 6.55 (t, J = 7.2 Hz, 1H), 4.65-4.53 (m, 3H), 4.09-4.05 (m, 5H), 3.77-3.70 (m, 1H), 3.54-3.53 (m, 1H), 2.98-2.96 (m, 4H), 1.30 (s, 6H), 1.24- 1.20 (m, 2H), 1.02-1.00 (m, 2H). LCMS (ESI): m z = 499.3 [M + H]⁺. 8 (R)-6-Cyano-N- (2-(2-fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl) picolinamide

¹H NMR (400 MHz, CDCl₃) δ 11.36 (s, 1H), 8.76 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.74 (s, 1H), 4.67-4.46 (m, 3H), 4.29-4.14 (m, 1H), 4.06 (t, J = 4.4 Hz, 4H), 3.73-3.66 (m, 1H), 3.00 (t, J = 4.4 Hz, 4H), 2.41 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 468.1 [M + H]⁺. 9 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-2- (pyridin-4-yl) oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 8.86 (d, J = 4.8 Hz, 2H), 8.72 (s, 1H), 8.46 (s, 1H), 7.94 (d, J = 4.8 Hz, 2H), 7.73 (s, 1H), 4.66- 4.46 (m, 3H), 4.27-4.14 (m, 1H), 4.07 (br s, 4H), 3.69- 3.65 (m, 1H), 3.02 (br s, 4H), 2.36 (s, 1H), 1.34 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 510.2 [M+H]+. 10 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-2-[(3S)-3- methylmorpholin- 4-yl]oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 8.71 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 4.63-4.44 (m, 3H), 4.21-4.04 (m, 3H), 3.98-3.95 (m, 4H), 3.80-3.77 (m, 2H), 3.72-3.63 (m, 3H), 3.52-3.44 (m, 1H), 2.96 (br s, 4H), 2.32 (s, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): mz = 532.2 [M + H]⁺. 11 N-[6- (Dimethylamino)- 2-[(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5-yl]-6- isopropoxy- pyridine-2- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.24 (s, 1H), 8.79 (s, 1H), 7.88-7.73 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 5.48-5.42 (m, 1H), 4.64-4.45 (m, 3H), 4.25-4.13 (m, 1H), 3.72-3.66 (m, 1H), 2.76 (s, 6H), 2.49 (br s, 1H), 1.47 (d, J = 5.2 Hz, 6H), 1.34 (s, 3H), 1.32 (3H each). LCMS (ESI): m/z = 459.2 [M + H]⁺. 12 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-4- hydroxypico- linamide

¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 8.67 (s, 1H), 8.46 (d, J = 4.4 Hz, 1H), 7.57-7.54 (m, 2H), 7.01 (s, 1H), 4.93 (s, 1H), 4.60-4.37 (m, 3H), 3.99-3.89 (m, 5H), 3.71- 3.69 (m, 1H), 2.92 (t, J = 4.4 Hz, 4H), 1.18 (s, 6H). LCMS (ESI): m z = 459.2 [M + H]⁺. 13 N-[6- (Dimethylamino)- 2-[(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5-yl]-6- pyrrolidin-3- yloxy-pyridine- 2-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.96 (s, 1H), 8.77 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.80-5.75 (m, 1H), 4.64-4.44 (m, 3H), 4.22-4.14 (m, 1H), 3.77-3.60 (m, 5H), 2.76 (s, 6H), 2.54-2.46 (m, 2H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 486.3 [M + H]⁺. 14 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-(5-methyl- pyridin-2-yl)- 1-oxoisoindolin- 5-yl)-2- methyloxazole- 5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 14.07 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 4.73-4.49 (m, 3H), 4.29-4.16 (m, 1H), 3.72-3.66 (m, 1H), 2.65 (s, 3H), 2.47 (s, 3H), 2.34 (s, 1H), 1.36 (s, 3H), 1.34 (s, 3 H). LCMS (ESI): m/z = 453.1 [M + H]⁺. 15 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-2- morpholino- oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H), 8.69 (s, 1H), 7.90 (s, 1H), 7.67 (s, 1H), 4.63-4.43 (m, 3H), 4.25-4.13 (m, 1H), 3.97-3.95 (m, 4H), 3.86-3.83 (m, 4H), 3.73-3.62 (m, 1H), 3.59-3.57 (m, 4H), 2.97-2.95 (m, 4H), 2.42 (s, 1H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 518.1 [M + H]⁺. 16 N-(2-((R)-2- fluoro-3- hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-2-((R)- 20-methyl- morpholino) oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 8.71 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 4.63-4.43 (m, 3H), 4.24-4.04 (m, 3H), 3.97 (t, J = 4.0 Hz, 4H), 3.80 (s, 2H), 3.71-3.66 (m, 3H), 3.51-3.48 (m, 1H), 2.96 (s, 4H), 2.37 (s, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 532.1 [M + H]⁺.

Example 17. (R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-6-(trifluoromethyl)picolinamide

a. 6-(Trifluoromethyl)picolinoyl Chloride

A solution of 6-(trifluoromethyl)picolinic acid (250 mg, 1.31 mmol) in thionyl chloride (4.75 mL, 65.4 mmol) was heated at 70° C. for 2 h. The mixture was concentrated and the crude product was used directly without purification.

b. (R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-6-(trifluoromethyl)picolinamide

To a solution of (R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one (218 mg, 0.65 mmol) in pyridine (1.5 mL) was added the crude 6-(trifluoromethyl)pyridine-2-carbonyl chloride (80 mg, 0.38 mmol). The reaction mixture was stirred at 26° C. for 2 h and concentrated. The residue was taken up in ethyl acetate (30 mL), washed with water (30 mL) and brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (eluting with 10% ethyl acetate in petroleum ether) to give (R)-N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-6-(trifluoromethyl)picolinamide (63 mg, 31%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 11.38; (s, 1H), 8.82; (s, 1H), 8.54; (d, J=8.4 Hz, 1H), 8.20-8.16; (m, 1H), 7.94; (d, J=7.6 Hz, 1H), 7.75; (s, 1H), 4.68-4.45; (m, 3H), 4.25-4.12; (m, 1H), 4.00; (t, J=4.4 Hz, 4H), 3.73-3.67; (m, 1H), 2.98; (br s, 4H), 2.41; (s, 1H), 1.35; (s, 3H), 1.32; (s, 3H). LCMS (ESI): m/z=511.2; [M+H]⁺.

The following compounds were prepared using a procedure similar to that described in Example 17.

Ex. Name Structure NMR, MS 18 (R)-N-(6- (Dimethyl- amino)-2-(2- fluoro-3- hydroxy-3- methylbutyl)-1- oxoisoindolin- 5-yl)-6- (trifluoro- methyl) picolinamide

¹H NMR (400 MHz, CDCl₃) δ 11.34 (s, 1H), 8.74 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.16 (t, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 4.65-4.45 (m, 3H), 4.23-4.15 (m, 1H), 3.73-3.68 (m, 1H), 2.80 (s, 6H), 2.46 (s, 1H), 1.35 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 469.1 [M + H]⁺. 19 N-[6-(Dimethyl- amino)-2-[(2R)- 2-fluoro-3- hydroxy-3- methyl-butyl]- 1-oxo- isoindolin- 5-yl]-6- methoxy- pyridine- 2-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.32 (s, 1H), 8.74 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.84-7.77 (m, 1H), 7.72 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.65-4.45 (m, 3H), 4.28-4.13 (m, 1H), 3.09 (s, 3H), 3.73-3.65 (m, 1H), 2.78 (s, 6H), 2.47 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 431.1 [M + H]⁺. 20 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoiso- indolin-5- yl)thieno [2,3-b] pyrazine-7- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.79 (s, 1H), 9.04 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 7.75 (s, 1H), 4.86-4.46 (m, 3H), 4.27-4.14 (m, 1H), 4.00 (t, J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.01 (t, J = 4.4 Hz, 4H), 2.43 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 500.2 [M + H]⁺. 21 22 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-6-[(1R)- 1-hydroxy- ethyl] pyridine-2- carboxamide and N-[2-[(2R)- 2-Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-6-[(1S)- 1-hydroxy- ethyl] pyridine-2- carboxamide (absolute stereochemistry assigned

Example 21, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 11.26 (s, 1H), 8.82 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 5.13-5.10 (m, 1H), 4.67-4.46 (m, 3H), 4.24- 4.15 (m, 1H), 4.06-3.94 (m, 4H), 3.71-3.65 (m, 1H), 3.29 (d, J = 4.4 Hz, 1H), 2.98 (t, J = 4.4 Hz, 4H), 2.43 (s, 1H), 1.65 (d, J = 6.4 Hz, 3H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 487.3 [M + H]⁺. Example 22, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 11.27 (s, 1H), 8.82 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 5.13-5.10 (m, 1H), 4.67-4.46 (m, 3H), 4.30- 4.13 (m, 1H), 4.02-3.99 (m, 4H), 3.71-3.65 (m, 1H), 3.28 (d, J = 4.4 Hz, 1H), 2.99 (t, J = 4.8 Hz, 4H), 2.43 (s, 1H), 1.65 (d, J = 6.4 Hz, 3H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m z = 487.2 [M + H]⁺. arbitrarily) 23 24 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-6-[(1R)-1- methoxyethyl] pyridine-2- carboxamide and N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-6-methoxy- ethyl]pyridine- 2-carboxamide (absolute stereochemistry assigned arbitrarily)

Example 23, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 8.83 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 4.66-4.46 (m, 4H), 4.28-4.13 (m, 1H), 4.03 (t, J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.39 (s, 3H), 3.05- 2.95 (m, 4H), 2.48 (s, 1H), 1.58 (d, J = 6.4 Hz, (s, 3H), 1.35, 1.33 (s, 3H). LCMS (ESI): m/z = 501.3 [M + H]⁺. Example 24, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 8.83 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 4.66-4.46 (m, 4H), 4.28-4.11 (m, 1H), 4.03 (t, J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.39 (s, 3H), 3.05- 2.95 (m, 4H), 2.48 (s, 1H), 1.58 (d, J = 6.4 Hz, 3H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 501.3 [M + H]⁺. 25 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-isopropoxy- 1-oxo- isoindolin-5- yl]pyrazolo [1,5-a] pyrimidine-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.26 (s, 1H), 8.83 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.66-4.50 (m, 3H), 4.46-4.14 (m, 1H), 4.00 (t, J = 4.4 Hz, 4H), 3.80-3.72 (m, 3H), 3.00 (t, J = 4.4 Hz, 4H), 2.30 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 525.2 [M + H]⁺. 26 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-5-methyl- 4-oxo- pyrazolo [1,5-a] pyrazine-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.22 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 7.67 (s, 1H), 7.62 (d, J = 5.6 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 4.62-4.43 (m, 3H), 4.21-4.13 (m, 1H), 3.98 (t, J = 4.4 Hz, 4H), 3.74-3.63 (m, 1H), 3.68 (s, 3H), 3.00 (t, J = 4.4 Hz, 4H), 2.43 (s, 1H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 513.2 [M + H]⁺. 27 N-[2-[(2R)- 2-Fluoro- 3-hydroxy- 3-methyl- butyl]-6- morpholino- 1-oxo- isoindolin-5- yl]-6-(1- hydroxy-1- methyl- ethyl) pyridine-2- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.14 (s, 1H), 8.82 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 4.68-4.46 (m, 3H), 4.29-4.15 (m, 2H), 3.99 (t, J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.00 (t, J = 4.4 Hz, 4H), 2.46 (s, 1H), 1.69 (s, 6H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 501.2 [M + H]⁺. 28 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-isopropoxy- 1-oxoiso- indolin-5- yl)-7-methyl- imidazo [1,2-b] pyridazine-3- carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 8.76 (s, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.37 (s, 1H), 4.98-4.88 (m, 2H), 4.57-4.37 (m, 3H), 4.01-3.87 (m, 1H), 3.73- 3.69 (m, 1H), 2.51 (s, 3H), 1.46 (d, J = 5.6 Hz, 6H), 1.18 (s, 6H). LCMS (ESI): m/z = 470.2 [M + H]⁺. 29 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoiso- indolin-5- yl)-7-methyl- imidazo [1,2-b] pyridazine-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 8.87 (s, 1H), 8.60 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.96 (br s, 1H), 7.75 (s, 1H), 4.65-4.46 (m, 3H), 4.28-4.14 (m, 1H), 4.00 (t, J = 4.4 Hz, 4H), 3.73-3.71 (m, 1H), 3.01 (t, J = 4.0 Hz, 4H), 2.59 (s, 3H), 2.38 (s, 1H), 1.34 (s, 3H), 1.33 (s, 3H). MS (ESI): m/z = 497.2 [M + H]⁺. 30 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-(4-(oxetan- 3-yl) piperazin-1- yl)-1-oxoiso- indolin-5- yl)thieno [2,3-b] pyrazine-7- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.67 (s, 1H), 9.04 (s, 1H), 8.84 (d, J = 2.4 Hz, 1H), 8.79 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 4.73- 4.45 (m, 7H), 4.25-4.15 (m, 1H), 3.69-3.62 (m, 2H), 3.07 (t, J = 4.4 Hz, 4H), 2.60 (br s, 4H), 2.43 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 555.1 [M + H]⁺. 31 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-(4-(oxetan- 3-yl) piperazin-1- yl)-1-oxoiso- indolin-5- yl)thieno [3,2-d) pyrimidine-7- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.87 (s, 1H), 9.44 (s, 2H), 9.13 (s, 1H), 8.78 (s, 1H), 7.77 (s, 1H), 4.73-4.45 (m, 7H), 4.25-4.15 (m, 1H), 3.69-3.62 (m, 2H), 3.09 (t, J = 4.4 Hz, 4H), 2.63 (br s, 4H), 2.38 (s, 1H), 1.33 (s, 3H), 1.26 (s, 3H). LCMS (ESI): mz = 555.1 [M + H]⁺. 32 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-1H-benz- imidazole-4- carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 12.55 (s, 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.05 (dd, J = 7.7, 1.1 Hz, 1H), 7.84 (dd, J = 8.0, 1.1 Hz, 1H), 7.55 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 4.90 (s, 1H), 4.63-4.35 (m, 3H), 4.05-3.87 (m, 5H), 3.71 (td, J = 15.6, 9.3 Hz, 1H), 2.99-2.90 (m, 4H), 1.23-1.15 (m, 6H). LCMS (ESI): m/z = 482.2 [M + H]⁺. 33 5-Chloro-N- [2-[(2R)-2- fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-1-methyl- pyrazole-4- carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.59 (s, 1H), 4.89 (s, 1H), 4.61-4.35 (m, 3H), 4.04- 3.86 (m, 4H), 3.83-3.77 (m, 4H), 3.77-3.64 (m, 1H), 2.91-2.85 (m, 4H), 1.18 (dd, J = 4.3, 1.7 Hz, 6H). LCMS (ESI): m z = 480.1 [M + H]⁺. 34 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoiso- indolin-5- yl)-[1,2,4] triazolo [1,5-a] pyridine-5- carboxamide

LCMS (ESI): m z = 483.2 [M + H]⁺.

Preparation of intermediate 6-(2,2,2-trifluoroethyl)pyridine-2-carboxylic Acid

a. 1-(6-Bromo-2-pyridyl)-2,2,2-trifluoro-ethanol

To a solution of 6-bromo-2-pyridinecarbaldehyde (2.0 g, 10.8 mmol) and cesium fluoride (2.4 g, 16.1 mmol) in tetrahydrofuran (10 mL) was added (trifluoromethyl)trimethylsilane (2.3 g, 16.1 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h, after which it was diluted with water (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-30% ethyl acetate in petroleum ether) to afford 1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethanol (1.5 g, 55%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.67; (t, J=8.0 Hz, 1H), 7.58; (d, J=8.0 Hz, 1H), 7.41; (d, J=7.6 Hz, 1H), 5.03; (quintet, J=6.8 Hz, 1H), 4.78; (d, J=7.6 Hz, 1H).

b. [1-(6-Bromo-2-pyridyl)-2,2,2-trifluoro-ethyl]methanesulfonate

To a solution of 1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethanol (500 mg, 1.95 mmol) and N,N-diisopropylethylamine (505 mg, 3.91 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (447 mg, 3.91 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min, diluted with water (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-30% ethyl acetate in petroleum ether) to afford [1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethyl] methanesulfonate (650 mg, 99%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.73-7.67; (m, 1H), 7.62-7.59; (m, 2H), 5.91; (q, J=6.0 Hz, 1H), 3.17; (s, 3H).

c. Ethyl 6-(2,2,2-trifluoroethyl)pyridine-2-carboxylate

To a solution of [1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethyl] methanesulfonate (600 mg, 1.80 mmol) in triethylamine (0.75 mL, 5.4 mmol) and ethanol (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (131 mg, 0.18 mmol). The reaction was stirred at 80° C. for 16 h under carbon monoxide (50 psi), filtered and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-10% ethyl acetate in petroleum ether) to afford ethyl 6-(2,2,2-trifluoroethyl)pyridine-2-carboxylate (400 mg, 96%) as a yellow oil. LCMS (ESI): m/z=234.0; [M+H]⁺.

d. 6-(2,2,2-Trifluoroethyl)pyridine-2-carboxylic Acid

To a solution of ethyl 6-(2,2,2-trifluoroethyl)pyridine-2-carboxylate (50 mg, 0.21 mmol) in water (1 mL) and ethanol (1 mL) was added lithium hydroxide monohydrate (18 mg, 0.43 mmol). The mixture was stirred at 25° C. for 2 h. The mixture was adjusted to pH=6 with 2 M hydrochloric acid and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over sodium sulfate, filtered and concentrated to afford 6-(2,2,2-trifluoroethyl)pyridine e-2-carboxylic acid (40 mg, 91%) as a white solid, which was used without purification.

Prepasration of Intermediate 5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylic Acid a. 4-Bromo-1H-pyrazole-5-carbonyl chloride

A solution of 4-bromo-1H-pyrazole-5-carboxylic acid (5.0 g, 26 mmol) in thionyl chloride (4.7 g, 39 mmol) was stirred at 100° C. for 3 h and concentrated to obtain crude 4-bromo-1H-pyrazole-5-carbonyl chloride (5.0 g, 91%) as a yellow solid, which was used directly.

b. 4-Bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide

To a solution of aminoacetaldehyde dimethyl acetal (2.7 g, 26 mmol) in dichloromethane (50 mL) was added 4-bromo-1H-pyrazole-5-carbonyl chloride (5.0 g, 24 mmol). The reaction mixture was stirred at 25° C. for 3 h and concentrated. The residue was purified by flash chromatography (eluting 0-10% methanol in dichloromethane) to afford 4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (6.1 g, 92%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 11.88 (br s, 1H), 7.67; (s, 1H), 7.30; (br s, 1H), 4.54; (t, J=5.2 Hz, 1H), 3.63; (t, J=5.2 Hz, 2H), 3.47; (s, 6H).

c. 3-Bromo-5H-pyrazolo[1,5-a]pyrazin-4-one

To a solution of 4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (3.0 g, 11 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.7 g, 13 mmol). The reaction was stirred at 25° C. for 16 h and concentrated. The residue was taken up in polyphosphoric acid (10 mL) and stirred at 145° C. for 5 h. Upon cooling to 0° C., the reaction mixture was quenched with aqueous ammonium hydroxide to pH=7, diluted with water (100 mL) and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with brine (100 mL×3), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-10% methanol in dichloromethane) to afford 3-bromo-5H-pyrazolo[1,5-a]pyrazin-4-one (860 mg, 37%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 7.86; (s, 1H), 7.58; (d, J=5.6 Hz, 1H), 6.81; (d, J=6.0 Hz, 1H).

d. 3-Bromo-5-methyl-pyrazolo[1,5-a]pyrazin-4-one

To a solution of 3-bromo-5H-pyrazolo[1,5-a]pyrazin-4-one (400 mg, 1.87 mmol) in tetrahydrofuran (5 mL) at 0° C. was added sodium hydride (90 mg, 2.24 mmol) in portions and stirred at 0° C. for 30 min. Iodomethane (0.17 mL, 2.8 mmol) was added dropwise, the reaction mixture was allowed to warm to 25° C. and stirred for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL), diluted with water (10 mL) and extracted with ethyl acetate (40 mL×2). The combined organic phase was concentrated and purified by flash chromatography (eluting gradient: 0-50% ethyl acetate in petroleum ether) to afford 3-bromo-5-methyl-pyrazolo[1,5-a]pyrazin-4-one (350 mg, 82%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.77; (s, 1H), 7.40; (d, J=6.0 Hz, 1H), 6.60; (d, J=6.0 Hz, 1H), 3.51; (s, 3H).

e. Ethyl 5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylate

To a solution of 3-bromo-5-methyl-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.32 mmol) in ethanol (20 mL) was added triethylamine (0.18 mL, 3.95 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (96.3 mg, 0.13 mmol). The reaction was stirred at 80 ° C. for 16 h under carbon monoxide (50 psi), filtered and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-10% methanol in dichloromethane) to afford ethyl 5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylate (80 mg, 28%) as a yellow solid. LCMS (ESI): m/z=222.0; [M+H]⁺.

f. 5-Methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylic acid

To a solution of ethyl 5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylate (60 mg, 0.27 mmol) in ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (23 mg, 0.54 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction was adjusted to pH=6 with 2 M hydrochloric acid and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with brine (10 mL×3), dried over sodium sulfate, filtered and concentrated to afford 5-methyl-4-oxo-pyrazolo[1,5 -a]pyrazine-3-carboxylic acid (45.0 mg, 86%) as a white solid, which was directly used in the next step without purification.

Preparation of intermediate 7-methylimidazo[1,2-b]pyridazine-3-carboxylic Acid

a. (E)-N,N-Dimethyl-N′-(5-methylpyridazin-3-yl)formimidamide

A solution of 5-methylpyridazin-3-amine (2.0 g, 18 mmol) in N,N-dimethylformamide dimethyl acetal (2.7 mL, 20 mmol) was stirred at 110° C. for 2 h and concentrated to afford N,N-dimethyl-N′-(5-methylpyridazin-3-yl)formamidine (3.0 g, quant.), which was used without purification.

b. Ethyl 2-(dimethylamino)-7-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-3-carboxylate

To a solution of N,N-dimethyl-N′-(5-methylpyridazin-3-yl)formamidine (3.0 g, 18 mmol) in acetonitrile (20 mL) was added ethyl bromoacetate (6.1 mL, 55 mmol). The mixture was stirred at 90° C. for 12 h and concentrated. The crude product was without purification. LCMS (ESI): m/z=251.1; [M+H]⁺.

c. Ethyl 7-methylimidazo[1,2-b]pyridazine-3-carboxylate

To a solution of ethyl 2-(dimethylamino)-7-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-3-carboxylate (4.9 g, 20 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (10 mL, 61 mmol). The mixture was stirred at 90° C. for 12 h, concentrated and purified by chromatography on silica (eluting gradient: 0-60% ethyl acetate in petroleum ether) to afford ethyl 7-methylimidazo[1,2-b]pyridazine-3-carboxylate (500 mg, 12%) as a yellow solid. LCMS (ESI): m/z=205.9; [M+H]⁺.

d. 7-Methylimidazo[1,2-b]pyridazine-3-carboxylic Acid

To a solution of ethyl 7-methylimidazo[1,2-b]pyridazine-3-carboxylate (300 mg, 1.46 mmol) in tetrahydrofuran (3 mL), water (3 mL) and methanol (1.5 mL) was added lithium hydroxide hydrate (123 mg, 2.92 mmol). The reaction mixture was stirred at 30° C. for 1 h. Hydrochloric acid (1 M) was added to adjust to pH=8-9. The solution was concentrated to afford crude 7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid as a yellow solid. LCMS (ESI): m/z=178; [M+H]⁺.

Preparation of Intermediate thieno[3,2-d]pyrimidine-7-carboxylic Acid

a. 7-Methylthieno[3,2-d]pyrimidine

To a suspension of 4-chloro-7-methylthieno[3,2-d]pyrimidine (500 mg, 2.71 mmol), triethylamine (0.75 mL, 5.42 mmol) in ethyl acetate (7.5 mL) and 2-propanol (1.5 mL) was added 20% palladium hydroxide on carbon (250 mg, 1.78 mmol). The reaction mixture was stirred at 15° C. under H₂ (15 psi) for 12 h. The mixture was filtered through a pad of Celite and washed with ethyl acetate (50 mL). The combined filtrate was concentrated to give 7-methylthieno[3,2-d] pyrimidine (400 mg, 98%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 9.25; (s, 2H), 7.66; (s, 1H), 2.54; (s, 3H).

b. 7-(Dibromomethyl)thieno[3,2-d]pyrimidine

A mixture of 7-methylthieno[3,2-d]pyrimidine (1.32 g, 8.79 mmol), 1-bromo-2,5-pyrrolidinedione (3.9 g, 22 mmol) and benzoyl peroxide (426 mg, 1.76 mmol) in carbon tetrachloride (80 mL) was stirred at 80° C. for 2.5 h. The mixture was concentrated in vacuum and purified by column chromatography (eluting gradient: 10% ethyl acetate in petroleum ether) to give 7-(dibromomethyl)thieno[3,2-d]pyrimidine (890 mg, 33%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 9.30; (s, 1H), 8.48; (s, 1H), 7.21; (s, 1H).

c. Thieno[3,2-d]pyrimidine-7-carbaldehyde

A mixture of 7-(dibromomethyl)thieno[3,2-d]pyrimidine (790 mg, 2.57 mmol) in water (20 mL) and pyridine (2 mL) was stirred at 100° C. for 1.5 h. The mixture was cooled to 15° C. and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over sodium sulfate, filtered and concentrated to give thieno[3,2-d]pyrimidine-7-carbaldehyde (420 mg, quant.) as a brown solid.

d. Thieno[3,2-d]pyrimidine-7-carboxylic Acid

To a mixture of thieno[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.61 mmol) in acetone (10 mL) and water (5 mL) was added sodium chlorite (165 mg, 1.83 mmol) and sulfamic acid (89 mg, 0.91 mmol) at 0° C. under nitrogen. The mixture was heated at 40° C. for 2 h and concentrated. The residue was washed with water (20 mL) and ethyl acetate (20 mL) to give thieno[3,2-d]pyrimidine-7-carboxylic acid (50 mg, 46%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.02; (br s, 1H), 9.62; (s, 1H), 9.27; (s, 1H), 9.18; (s, 1H).

Preparation of Intermediate 1-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

To a solution of potassium hydroxide (1.6 g, 29 mmol) in water (3 mL) was added a solution of 2-oxo-1,2-dihydropyridine-3-carboxylic acid (2.0 g, 14 mmol) in methanol (30 mL) at 10° C. After 10 min, ethyl iodide (2.5 g, 16 mmol) was added to the white mixture, and the reaction stirred at 70° C. for 20 h. The mixture was concentrated to remove methanol, and pH was to 2-3 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 1-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (400 mg, 2.1 mmol, 15% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 14.41; (s, 1H), 8.52; (d, J=6.8 Hz, 1H), 7.66; (m, 1H), 6.58; (m, 1H), 4.16; (q, J=7.2 Hz, 2H), 1.46; (t, J=7.2 Hz, 3H). LCMS (ESI): m/z=168.1; [M+H]⁺.

Preparation of Intermediate 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

a. Ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate

Sulfuric acid (1.2 mL, 22) was added dropwise to a solution of 2-oxo-1,2-dihydropyridine-3-carboxylic acid (6 g, 43 mmol) in ethanol (200 mL) at 10° C., and the mixture was heated and stirred at 90° C. for 12 h. The reaction mixture was brought to room temperature, adjusted to pH=7-8 with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (300 mL×5). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (dichloromethane:methanol=100:1 to 10:1) to give ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (3 g, 18 mmol, 42% yield) as a white solid. LCMS (ESI): m/z =168.1; [M+H]⁺.

b. Ethyl 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate

A solution of ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (1 g, 6 mmol) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (1.7 g, 15 mmol) at 10° C. 2-Iodopropane (5.4 mL, 54 mmol) was added to the white mixture at 0° C., and the reaction mixture was stirred at 80° C. for 4 h. The mixture was adjusted to pH=2-3 with 1 N hydrochloric acid and extracted with ethyl acetate (30 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give ethyl 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (400 mg, 1.9 mmol, 32% yield).

c. 1-Isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

To a mixture of ethyl 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (400 mg, 1.9 mmol) in ethanol (2 mL) was added a mixture of sodium hydroxide (153 mg, 3.82 mmol) in water (500 uL) at 10° C. The reaction mixture was stirred at 10° C. for 8 h, after which it was extracted with ethyl acetate (10 mL×2). The aqueous layer was adjusted to pH=2˜3 with 1 N hydrochloric acid and extracted with ethyl acetate (10 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated to give 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 51% yield) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 14.55; (s, 1H), 8.49; (d, J =7.2 Hz, 1H), 7.72; (d, J=5.2 Hz, 1H), 6.63; (t, J=6.8, 1H), 5.38-5.28; (m, 1H), 1.46; (d, J=6.8 Hz, 6H).

Preparation of intermediate 1-Cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

a. Ethyl 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate

To the mixture of ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (1.2 g, 7.2 mmol) in toluene (20 mL) was added cyclopropylboronic acid (1.2 g, 14 mmol), copper (II) acetate (1.3 g, 7.2 mmol), followed by pyridine (2.9 mL, 36 mmol) and sodium bis(trimethylsilyl)amide (1 M, 7.2 mL) under oxygen. The mixture was stirred at 100° C. under an oxygen atmosphere (15 psi) for 24 h. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give ethyl 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 17% yield) as a white solid. LCMS (ESI): m/z=208.2; [M+H]⁺.

b. 1-Cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

To a mixture of ethyl 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 1.45 mmol) in ethanol (2 mL) was added a mixture of sodium hydroxide (120 mg, 2.9 mmol) in water (500 uL) at 12° C. The mixture was stirred at 12° C. for 8 h, after which it was extracted with ethyl acetate (10 mL×2). The aqueous layer was adjusted to pH=2˜3 with 1 N hydrochloric acid solution and extracted with ethyl acetate (10 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated to give 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (150 mg, 0.67 mmol, 46% yield) as a light yellow solid. LCMS (ESI): m/z=180.1; [M+H]⁺.

Biological Examples

Compounds were assayed for inhibition of human IRAK4 and IRAK1 catalytic activity using recombinant enzyme produced from insect cells. Full-length IRAK4 protein, carrying an N-terminal His6-Tag, was obtained from Life Technologies (Carlsbad, CA, USA). The IRAK1 construct was produced internally and was comprised of IRAK1 residues Arg194 to Ser712, preceded by an NH2-terminal His6 tag and the coding sequence for glutathione-S-transferase.

Kinase activities were assayed using the Transcreener-Fluorecescence polarization platform (BelBrook Labs, Madison, Wis., USA) that measures amounts of the reaction product, ADP. The IRAK4 reaction conditions were optimized using an IRAK1-derived peptide (sequence H-KKARFSRFAGSSPSQSSMVAR) to provide a linear reaction rate over the course of a 90 min incubation, which resulted in 10-12% conversion of the starting ATP to ADP. Final IRAK4 assay conditions were 1.25 nM IRAK4; 125 μM ATP; 10 μM MgCl2; 125 μM peptide in reaction buffer (25 mM HEPES (pH7.4); 2 mM Dithiothreitol; 0.015% Brij-35; and 0.5% dimethyl sulfoxide. The IRAK1 activity was optimized similarly, yielding final assay conditions of 1.5 nM IRAK1; 62.5 μM ATP; 5 μM MgCl2, and 62.5 μM IRAK1 peptide in reaction buffer for 60 min.

Assays of compounds for kinase inhibition were performed using inhibitors serially-diluted in dimethyl sulfoxide, which was accomplished with a LabCyte Echo 555 liquid dispenser. 384 well assay plates spotted with compound received 4 μl of a 2× substrate (ATP+peptide) mix in reaction buffer, followed by 4 μl of 2× enzyme diluted in reaction buffer. Reactions were halted at 60 (IRAK1) or 90 (IRAK4) min by addition of 6μl of detection buffer, containing EDTA (40 nM final concentration), 0.95 μg of the ADP-binding antibody ADP2, ADP tracer (3 nM final concentration), and 25 μM HEPES. Following a 1 hr incubation, fluorescence polarization of the ADP2-antibody:TRACER complex was read on a Tecan M1000 plate reader using a 635/20 excitation filter in combination with a 670/20 emission filter. Delta milli-P values were analyzed using Genedata software to fit dose-response curves and compute compound Ki values, using ATP Km values of 642 μm and 83.2 μM for IRAK4 and IRAK1, respectively. Table 2 provides IRAK4 Ki values for representative compounds of the present invention.

TABLE 2 IRAK4 Ki values of representative compounds of the present invention. IRAK4 Ki Example (uM) 1 0.0051 2 0.0032 3 0.0082 4 0.008 5 0.0056 6 0.0099 7 0.0064 8 0.0039 9 0.00068 10 0.0076 11 0.021 12 0.27 13 0.0058 14 0.0042 15 0.0046 16 0.007 17 0.0025 18 0.0011 19 0.0015 20 0.0023 21 0.0017 22 0.0092 23 0.012 24 0.033 25 0.0065 26 0.047 27 0.0096 28 0.00082 29 0.0052 30 0.0033 31 0.005 32 0.0011 33 0.051 34 0.0028

The features disclosed in the foregoing description, or the following claims, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof.

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

The patents, published applications, and scientific literature referred to herein establish the knowledge of those skilled in the art and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually. 

What is claimed is:
 1. A compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof, R¹ is C₁₋₆alkoxy, oxetanyl, —NR^(x)R^(y), or a 6-membered heteroaryl that is optionally substituted with R^(z); R² is halogen, oxo, CN, OH, C₁₋₆alkyl, —(C₀₋₃alkyl)-C₃₋₆cycloalkyl group, a —(C₀₋₃alkyl)-3-11 membered heterocyclic group, —NR^(a)R^(b), —NR^(e)C(O)R^(f), —NR^(e)S(O)₁₋₂R^(f), —C(O)(C₁₋₃alkyl), —C(O)NR^(c)R^(d), —C(O)OR^(f), —S(O)₁₋₂NR^(c)R^(d), or —(C₀₋₃alkyl)-OP(O)(OC₁₋₃alkyl)₂, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen; oxo; CN; OR^(f); C₁₋₃haloalkoxy; —C(O)(C₁₋₃alkyl); —S—C₁₋₃alkyl; or C₁₋₃alkyl optionally substituted with OH, halogen, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, or a 3-8 membered heterocyclic group, ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 6-membered saturated or partially saturated heterocyclic group, or a 9-membered bicyclic heteroaryl that comprises at least two heteroatoms selected form the group consisting of N, O, and S, wherein ring A is optionally substituted with R^(m); provided ring A is not an optionally substituted 9-membered bicyclic heteroaryl of the following formula,

R^(a), R^(b),R^(c) and R^(d) are, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), or —S(O)₁₋₂R^(f), or R^(c) and R^(d) are taken together to form a 5-8 membered heterocyclic group, wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(f), —NR^(g)R^(h), or a 5-6 membered monocyclic heteroaryl ring; R^(e) is, independently at each occurrence, hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy; R^(f) is, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, —OR^(e), or —NR^(g)R^(h); R^(g) and R^(h) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy; each R^(m) is, independently at each occurrence, halogen; oxo; CN; —OR^(v); —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C₁₋₃alkyl; R^(n), R^(p), R^(r) and R^(s) are, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R^(v), —C(O)OR^(v), —C(O)NR^(t)R^(u), or —S(O)₁₋₂R^(v), or R^(r) and R^(s) are taken together to form a 5-8 membered heterocyclic group, wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(v), —NR^(t)R^(u), or a 5-6 membered monocyclic heteroaryl ring; R^(t) and R^(u) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy; R^(v) is, independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(w), or —NR^(t)R^(u); and R^(w) is, independently at each occurrence, hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy; R^(x) and R^(y) are, independently at each occurrence, C₁₋₆alkyl, or R^(x) and R^(y) are taken together to form a 6-membered heterocyclic group that is optionally substituted with R^(z); each R^(z) is, independently at each occurrence, halogen; oxo; CN; —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(n)R^(p); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃ alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C₁₋₃alkyl.
 2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R¹ is —NR^(x)R^(y).
 3. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R^(x) and R^(y) are taken together to form a 6-membered heterocyclic group that is optionally substituted with R^(z).
 4. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R^(x) and R^(y) are taken together to form a morpholino group that is optionally substituted with R^(z).
 5. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 1e is a 6-membered heteroaryl that is optionally substituted with R^(z).
 6. The compound or salt of claim 5 wherein 1e is pyridyl that is optionally substituted with R^(z).
 7. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 1e is selected from the group consisting of


8. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 1e is


9. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 1e is


10. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of


11. The compound of claim 10, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of


12. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R^(m) is selected from the group consisting of chloro, oxo, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CN, methoxy, OH, isopropoxy, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-methoxyethyl, 2-hydroxyprop-2-yl, morpholino, 20methylmorpholino, and 1H-pyrrol-3-yloxy.
 13. The compound of claim 1, selected from the group consisting of

or a stereoisomer or pharmaceutically acceptable salt thereof.
 14. A pharmaceutical composition comprising a compound of a claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
 15. A method of preventing, treating, or lessening the severity of a disease or condition responsive to the inhibition of IRAK4 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.
 16. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.
 17. A method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.
 18. The method of claim 17, wherein the disease is selected from the group consisting of Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.
 19. A method for treating endometriosis in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.
 20. A method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of acute kidney injury, acute respiratory distress syndrome, acute lung injury, adult onset Still's disease, allergic airway syndrome, allergic rhinitis, allograft rejection, asthma, atherosclerosis, atopic dermatitis, bronchitis, calcium pyrophosphate deposition disease (CPPD) also known as pseudo gout, cerebrovascular accident (e.g., stroke), chronic kidney disease, chronic obstructive pulmonary disease (COPD), contact dermatitis, Crohn's disease, cryopyrin-associated periodic syndromes (CAPS), cutaneous lupus, delayed hypersensitivity, diabetes, endometriosis, gout, gouty arthritis, graft vs host disease, graft rejection, inflammatory bowel disease (IBD), inflammatory myositis (e.g., polymyositis, dermatomyositis), interstitial lung disease, lupus, lupus nephritis, metabolic syndrome, multiple sclerosis, neurodegeneration, neuropathic pain, non-alcoholic fatty liver disease, obesity, psoriasis, rheumatoid arthritis, rhinitis, scleroderma, sepsis, Sjogren's syndrome, systemic lupus erythematosus, systemic onset juvenile idiopathic arthritis, systemic sclerosis and ulcerative colitis
 21. A method of inhibiting IRAK4 in a cell, ex vivo, comprising contacting the cell with a compound according to claim 1, or a stereoisomer or salt thereof.
 22. A method of inhibiting IRAK4 in a patient in need of therapy, comprising administering to the patient a compound of claim
 1. 23. Use of a compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, to inhibit IRAK4. 